Correspondence
Disorders of the Autonomic Nervous System
N Engl J Med 1997; 337:278-280July 24, 1997
- Article
To the Editor:
In October 1995, a committee composed of members of the American Autonomic Society and members of the American Academy of Neurology met to develop consensus definitions of multiple-system atrophy (the Shy–Drager syndrome) and pure autonomic failure (idiopathic orthostatic hypotension, progressive autonomic failure, and the Bradbury–Eggleston syndrome). The previous nosologic classification, particularly the use of the term Shy–Drager syndrome, was misleading and did not reflect current knowledge about autonomic disorders. Although the scheme presented was not perfect, it is consistent with present information about these varied, complicated conditions.1,2
Goldstein et al. (March 6 issue)3 propose a new classification of autonomic disorders based on their studies of the uptake of fluorodopamine by the heart. Although these data are interesting, they add little to our understanding of these disorders; they do reflect a more technologically sophisticated approach that shows a neuropharmacologic difference between central and peripheral lesions of the sympathetic nervous system. These data, however, do not justify a reclassification of autonomic dysfunction.
We are concerned about two issues: first, the relatively small numbers of patients on which Goldstein et al. base their conclusions; and second, definitions that appear to be inappropriate and to have questionable diagnostic validity. Goldstein et al. describe three patients with “pure autonomic failure,” two of whom had uncharacteristic plasma norepinephrine levels that were nearly normal when the patients were supine. This in itself raises doubt about the validity of the diagnosis. These patients with pure autonomic failure would certainly be considered atypical.
Goldstein et al. criticize the consensus committee's distinction between Parkinson's disease with autonomic failure and multiple-system atrophy, based on the response to levodopa, but their comments are based on only two patients with Parkinson's disease who had “sympathetic neurocirculatory failure.” They conclude that the distinction between the Shy–Drager syndrome and multiple-system atrophy is based on the presence of parasympathetic failure in multiple-system atrophy and its absence in the Shy–Drager syndrome, but they offer no data to support this contention. In fact, all studies based on reasonably large numbers of patients have found parasympathetic failure in most patients with the Shy–Drager syndrome.4
There is little debate about the need to refine the traditional classification of these syndromes. However, it is inappropriate to derive a general scheme of classification from experience with so few patients of each type, particularly when some appear to have atypical clinical or neurochemical characteristics.
The classification of dysautonomias is dynamic and ongoing; as new data accumulate, there will be modifications and even major changes. Unfortunately, Dr. Goldstein and colleagues do not provide sufficiently persuasive evidence to change the present classification. Their criticism of the consensus statement is unwarranted.
4 ReferencesIrwin J. Schatz, M.D.
Phillip Low, M.D.
Ronald J. Polinsky, M.D.
American Autonomic Society, Honolulu, HI 968131
The Consensus Committee of the American Autonomic Society and the American Academy of Neurology
Web of Science | Medline2
Schatz IJ . Farewell to the “Shy Drager syndrome.“ Ann Intern Med 1996;125:74-75
Web of Science | Medline3
Goldstein DS ,Holmes C ,Cannon RO III ,Eisenhofer G ,Kopin IJ . Sympathetic cardioneuropathy in dysautonomias. N Engl J Med 1997;336:696-702
Full Text | Web of Science | Medline4
Polinsky RJ ,Kopin IJ ,Ebert MH ,Weise V . Pharmacologic distinc-tion of different orthostatic hypotension syndromes. Neurology 1981;31:1-7
Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: Schatz et al. question the pathophysiologic classification we proposed. Actually, our classification largely agrees with the one in the consensus statement by the American Autonomic Society.1 The report proposed differentiating subgroups of patients with multiple-system atrophy pathophysiologically, on the basis of the occurrence of sympathetic neurocirculatory failure (persistent orthostatic hypotension and characteristic blood-pressure responses during and after the Valsalva maneuver). The findings in patients with the Shy–Drager syndrome (multiple-system atrophy with sympathetic neurocirculatory failure) clearly indicated that that syndrome differed from multiple-system atrophy without sympathetic neurocirculatory failure.
The consensus statement considered multiple-system atrophy with parkinsonism to differ from Parkinson's disease with autonomic failure, on the basis of the clinical responsiveness to levodopa. Our report distinguished these conditions pathophysiologically. All 13 patients with multiple-system atrophy had a normal or increased rate of entry of norepinephrine into the cardiac venous drainage (cardiac norepinephrine spillover) and normal or increased myocardial 6-[18F]fluorodopamine–derived radioactivity, whereas both patients with Parkinson's disease and sympathetic neurocirculatory failure had no cardiac norepinephrine spillover and no myocardial 6-[18F]fluorodopamine–derived radioactivity. These findings definitively established that there was cardiac sympathetic denervation in the latter group but not the former.
The report also showed that patients with pure autonomic failure can have cardiac sympathetic denervation despite normal plasma norepinephrine levels. The finding of below-normal norepinephrine concentrations in only one of the three patients in our study did not render this group atypical. Indeed, plasma norepinephrine concentrations are a quite imperfect neurochemical means of diagnosing pure autonomic failure, even on the basis of orthostatic changes.2-4
The diagram of the pathophysiologic classification (Figure 3 of our article) was potentially confusing, since the algorithm could be taken to imply that patients with the Shy–Drager syndrome have sympathetic neurocirculatory failure but not concurrent parasympathetic failure. We did not intend to imply this. In our series, most of the patients with the Shy–Drager syndrome had constipation, urinary retention, impotence, abnormal sweating, or decreased heart-rate responses, all symptoms and signs attributable to diffuse parasympathetic failure. The accompanying diagram (Figure 1Figure 1
Pathophysiologic Classification of Dysautonomias Based on the Presence or Absence of Sympathetic Neurocirculatory Failure, the Occurrence of Signs of Central Neurodegeneration, and Clinical Responsiveness to Levodopa–Carbidopa.) shows the classification more clearly.In sum, our results generally provided pathophysiologic evidence to support the clinical classification scheme in the consensus statement, but with the initial distinguishing characteristic of the presence or absence of sympathetic neurocirculatory failure. What we have proposed is a refinement rather than a replacement of the classification scheme in the consensus statement.
4 ReferencesDavid S. Goldstein, M.D., Ph.D.
Graeme Eisenhofer, Ph.D.
Irwin J. Kopin, M.D.
National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892-14241
The Consensus Committee of the American Autonomic Society and the American Academy of Neurology
Web of Science | Medline2
Goldstein DS ,Polinsky RJ ,Garty M , et al. Patterns of plasma levels of catechols in neurogenic orthostatic hypotension. Ann Neurol 1989;26:558-563
CrossRef | Web of Science | Medline3
Esler M ,Jackman G ,Bobik A , et al. Determination of norepinephrine apparent release rate and clearance in humans. Life Sci 1979;25:1461-1470
CrossRef | Web of Science | Medline4
Meredith IT ,Eisenhofer G ,Lambert GW ,Jennings GL ,Thompson J ,Esler MD . Plasma norepinephrine responses to head-up tilt are misleading in autonomic failure. Hypertension 1992;19:628-633
Web of Science | Medline
- Citing Articles (1)
Citing Articles
1
Samir M Parikh, André Diedrich, Italo Biaggioni, David Robertson. (2002) The nature of the autonomic dysfunction in multiple system atrophy. Journal of the Neurological Sciences 200:1-2, 1-10
CrossRef
